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TP63-mediated enhancer reprogramming drives the squamous subtype of pancreatic ductal adenocarcinoma (ChIP-seq)

ABSTRACT: The aberrant expression of squamous lineage markers in pancreatic ductal adenocarcinoma (PDA) has been correlated with poor clinical outcomes. However, the functional role of this putative trans-differentiation event in PDA pathogenesis remains unclear. Here, we show that expression of the transcription factor TP63 (ΔN isoform) is sufficient to install and sustain the enhancer landscape and transcriptional signature of the squamous lineage in human PDA cells. In addition, we demonstrate that TP63-driven enhancer reprogramming promotes aggressive tumor phenotypes, including enhanced cell motility and invasion and an accelerated growth of primary PDA tumors and metastases in vivo. Conversely, we provide evidence that squamous PDA remains addicted to TP63 to sustain the growth of primary tumors and metastases. Taken together, our study validates the functional significance of squamous trans-differentiation in PDA, and reveals TP63-based reprogramming of PDA cells as an experimental tool for investigating vulnerabilities linked to this cell fate transition.

ORGANISM(S): Homo sapiens

PROVIDER: GSE115461 | GEO | 2018/11/13

REPOSITORIES: GEO

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TP63-mediated enhancer reprogramming drives the squamous subtype of pancreatic ductal adenocarcinoma

Project description:The aberrant expression of squamous lineage markers in pancreatic ductal adenocarcinoma (PDA) has been correlated with poor clinical outcomes. However, the functional role of this putative trans-differentiation event in PDA pathogenesis remains unclear. Here, we show that expression of the transcription factor TP63 (ΔN isoform) is sufficient to install and sustain the enhancer landscape and transcriptional signature of the squamous lineage in human PDA cells. In addition, we demonstrate that TP63-driven enhancer reprogramming promotes aggressive tumor phenotypes, including enhanced cell motility and invasion and an accelerated growth of primary PDA tumors and metastases in vivo. Conversely, we provide evidence that squamous PDA remains addicted to TP63 to sustain the growth of primary tumors and metastases. Taken together, our study validates the functional significance of squamous trans-differentiation in PDA, and reveals TP63-based reprogramming of PDA cells as an experimental tool for investigating vulnerabilities linked to this cell fate transition.

2018-11-13 | GSE115463 | GEO

TP63-mediated enhancer reprogramming drives the squamous subtype of pancreatic ductal adenocarcinoma (RNA-seq)

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Squamous trans-differentiation of pancreatic cancer cells promotes stromal inflammation (RNA-seq)

Project description:A highly aggressive subset of pancreatic ductal adenocarcinomas undergo trans-differentiation into the squamous lineage during disease progression. While the tumorigenic consequences of this aberrant cell fate transition are poorly understood, recent studies have identified a role for the master regulator TP63 in this process. Here, we investigated whether squamous trans- differentiation of pancreatic cancer cells can influence the phenotype of non-neoplastic cells in the tumor microenvironment. Conditioned media experiments revealed that squamous-subtype pancreatic cancer cells secrete factors that convert quiescent pancreatic stellate cells into a specialized subtype of cancer-associated fibroblasts (CAFs) that express inflammatory genes at high levels. We use gain- and loss-of-function approaches in vivo to show that squamous-subtype pancreatic tumor models become enriched with inflammatory CAFs and neutrophils in a TP63- dependent manner. These non cell-autonomous effects occur, at least in part, through TP63- mediated activation of enhancers at pro-inflammatory cytokine loci, which includes IL1A as a key target. Taken together, our findings reveal enhanced tissue inflammation as a consequence of squamous trans-differentiation in pancreatic cancer, thus highlighting an instructive role of tumor cell lineage in reprogramming the stromal microenvironment.

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Targeting IL13Ralpha2 activates STAT6-TP63 pathway to suppress breast cancer lung metastasis

Project description:IL13Rα2 overexpression promotes metastasis of basal-like breast cancers IL13Rα2 depletion in highly metastatic breast cancer cells suppresses lung metastases formation by upregulating TP63 and decreasing their migratory potential

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Genome wide characterization reveals complex interplay between TP53 and TP63 in response to genotoxic stress [ChIP-Seq]

Project description:In response to genotoxic stress the TP53 tumour suppressor activates target gene expression to induce cell cycle arrest or apoptosis depending on the extent of DNA damage. These canonical activities can be repressed by TP63 in normal stratifying epithelia to maintain proliferative capacity or drive proliferation of squamous cell carcinomas, where TP63 is frequently overexpressed/amplified. Here we use ChIP-sequencing, integrated with microarray analysis, to define the genome wide interplay between TP53 and TP63 in response to genotoxic stress in normal cells. We reveal that TP53 and TP63 bind to overlapping, but distinct cistromes of sites through utilization of distinctive consensus motifs and that TP53 is constitutively bound to a number of sites. We demonstrate that cisplatin and adriamycin elicit distinct effects on TP53 and TP63 binding events, through which TP53 can induce or repress transcription of an extensive network of genes by direct binding and/or modulation of TP63 activity. Collectively, this results in a global TP53 dependent repression of cell cycle progression, mitosis and DNA damage repair concomitant with activation of anti-proliferative and pro-apoptotic canonical target genes. Further analyses reveals that in the absence of genotoxic stress TP63 plays an important role in maintaining expression of DNA repair genes, loss of which results in defective repair Examination of p63 and p53 binding sites in neonatal foreskin keratinocytes in response to adriamycin or cisplatin treatment

2014-04-11 | E-GEOD-56674 | biostudies-arrayexpress

TP53 and TP63 modulation of Squamous PDAC

Project description:TP53 and TP63 modulation of Squamous PDAC

| PRJEB12635 | ENA

Genome wide characterization reveals complex interplay between TP53 and TP63 in response to genotoxic stress [Affymetrix]

Project description:In response to genotoxic stress the TP53 tumour suppressor activates target gene expression to induce cell cycle arrest or apoptosis depending on the extent of DNA damage. These canonical activities can be repressed by TP63 in normal stratifying epithelia to maintain proliferative capacity or drive proliferation of squamous cell carcinomas, where TP63 is frequently overexpressed/amplified. Here we use ChIP-sequencing, integrated with microarray analysis, to define the genome wide interplay between TP53 and TP63 in response to genotoxic stress in normal cells. We reveal that TP53 and TP63 bind to overlapping, but distinct cistromes of sites through utilization of distinctive consensus motifs and that TP53 is constitutively bound to a number of sites. We demonstrate that cisplatin and adriamycin elicit distinct effects on TP53 and TP63 binding events, through which TP53 can induce or repress transcription of an extensive network of genes by direct binding and/or modulation of TP63 activity. Collectively, this results in a global TP53 dependent repression of cell cycle progression, mitosis and DNA damage repair concomitant with activation of anti-proliferative and pro-apoptotic canonical target genes. Further analyses reveals that in the absence of genotoxic stress TP63 plays an important role in maintaining expression of DNA repair genes, loss of which results in defective repair Examination of gene expression levels of HFKS siRNA depleted for p53 or p63 in response to adriamycin or cisplatin treatment We analyzed RNA using the Affymetrix Human Exon 1.0 ST platform. Array data was processed using the AltAnalyze.

2014-04-30 | E-GEOD-57187 | biostudies-arrayexpress

TP63-mediated enhancer reprogramming drives the squamous subtype of pancreatic ductal adenocarcinoma

Project description:TP63-mediated enhancer reprogramming drives the squamous subtype of pancreatic ductal adenocarcinoma

| PRJNA475105 | ENA

Targeting IL13Ralpha2 activates STAT6-TP63 pathway to suppress breast cancer lung metastasis

Project description:IL13R?2 overexpression promotes metastasis of basal-like breast cancers IL13R?2 depletion in highly metastatic breast cancer cells suppresses lung metastases formation by upregulating TP63 and decreasing their migratory potential MCF10CA1a (MIV) cells expressing the luciferase gene (MIV-Luc), were stably transduced with lentiviral constructs expressing either scrambled shRNA or shRNA against IL13R?2. The two cell lines were then either mock treated or treated with 20ng/ml IL13 for 16h followed by RNA isolation. Gene expression analysis was performed using the Affymetrix Human Exon 1.0 ST platform. Array data was processed by Affymetrix Exon Array Computational Tool.

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